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Protocol for the Examination of Specimens From Patients With Uveal Melanoma.

A Basis for Checklists

This protocol is intended to assist pathologists in providing clinically useful and relevant information as a result of the examination of surgical specimens. Use of this protocol is intended to be entirely voluntary. If equally valid protocols or similar documents are applicable, the pathologist is, of course, free to follow those authorities. Indeed, the ultimate judgment regarding the propriety of any specific procedure must be made by the physician in light of the individual circumstances presented by a specific patient or specimen.

It should be understood that adherence to this protocol will not guarantee a successful result. Nevertheless, pathologists are urged to familiarize themselves with the document. Should a physician choose to deviate from the protocol based on the circumstances of a particular patient or specimen, the physician is advised to make a contemporaneous written notation of the reason for the procedure followed.

The College recognizes that this document may be used by hospitals, attorneys, managed care organizations, insurance carriers, and other payers. However, the document was developed solely as a tool to assist pathologists in the diagnostic process by providing information that reflects the state of relevant medical knowledge at the time the protocol was first published. It was not developed for credentialing, litigation, or reimbursement purposes. The College cautions that any uses of the protocol for these purposes involve considerations that are beyond the scope of this document.

PROTOCOL FOR THE EXAMINATION OF SPECIMENS FROM PATIENTS WITH UVEAL MELANOMA
I. Cytologic Material
 A. Clinical information
 1. Patient identification
 a. Name
 b. Identification number
 c. Age (birth date)
 d. Gender
 2. Responsible physician(s)
 3. Date of procedure
 4. Other clinical information
 a. Relevant history
 (1) Clinical findings
 (2) Past ocular history
 (3) Previous ocular surgery
 (4) Previous treatment
 b. Relevant findings (eg, liver function tests,
 ultrasound)
 c. Clinical diagnosis
 d. Procedure (eg, fine-needle aspiration, anterior
 chamber paracentesis)
 e. Operative findings
 f. Anatomic site (right or left eye; part of eye
 sampled)
 B. Macroscopic examination
 1. Specimen
 a. Unfixed/fixed (specify fixative)
 b. Number of slides received
 c. Quantity and appearance of fluid specimen
 d. Other (eg, core of tissue in needle shaft)
 e. Intraoperative/intraprocedural consultation
 2. Material submitted for microscopic evaluation
 (eg, cytocentrifuge, smear, filter preparation)
 3. Material submitted for special studies (specify)
 (eg, immunocytochemistry)
 C. Microscopic evaluation
 1. Adequacy of specimen for evaluation (if unsatisfactory
 for evaluation, specify reason)
 2. Tumor, if present
 a. Histologic type, if possible (note A)
 b. Other characteristics (note B)
 (1) Presence of pigment
 (2) Cytoplasmic indentation of nucleus
 (3) Cytoplasmic vacuolization
 3. Additional pathologic findings, if present (eg,
 presence of retinal tissue, inflammatory cells)
 4. Results/status of special studies (specify)
 5. Comments
 a. Correlation with intraprocedural consultation
 b. Correlation with other specimens, as appropriate
 c. Correlation with clinical information, as
 appropriate
II. Biopsy
 A. Clinical information
 1. Patient identification
 a. Name
 b. Identification number
 c. Age (birth date)
 d. Gender
 2. Responsible physician(s)
 3. Date of procedure
 4. Other clinical information
 a. Relevant history
 (1) Clinical findings
 (2) Past ocular history
 (3) Previous ocular surgery
 (4) Previous treatment
 b. Relevant findings (eg, liver function tests,
 ultrasound)
 c. Procedure (eg, peripheral iridectomy, iridocyclectomy,
 sclerouveectomy)
 d. Operative findings
 e. Anatomic site of specimen (right or left
 eye)
 B. Macroscopic examination
 1. Specimen
 a. Unfixed/fixed (specify fixative)
 b. Orientation (if indicated by surgeon by
 written instruction, diagram, or suture);
 ink margins of excisional biopsy specimens
 c. Previously opened
 d. Number of pieces
 e. Size(s) (3 dimensions, if possible)
 f. Tumor
 (1) Size (3 dimensions, if possible)
 (2) Presence of necrotic tissue
 (3) Descriptive features
 g. Other tissues, as appropriate
 h. Results of intraoperative consultation
 2. Tissue submitted for microscopic evaluation
 (specify)
 3. Special studies (specify) (eg, special histochemical
 stains, immunohistochemical stains)
 C. Microscopic evaluation
 1. Tumor
 a. Histologic type (note A)
 b. Histologic grade
 c. Extent
 (1) Involvement of adjacent structures,
 such as ciliary body
 (2) Extraocular extension
 (3) Invasion of normal vessels or tumor
 vessels
 d. Other prognostic features (note B)
 2. Additional pathologic findings, if present
 a. Drusen
 b. Neovascularization
 c. Nevus
 d. Ectropion uveae
 e. Other(s)
 3. Results/status of special studies (specify)
 4. Comments
 a. Correlation with intraoperative consultation
 b. Correlation with other specimens, as appropriate
 c. Correlation with clinical information, as
 appropriate
III. Resection Specimen (Globe)
 A. Clinical information
 1. Patient identification
 a. Name
 b. Identification number
 c. Age (birth date)
 d. Gender
 2. Responsible physician(s)
 3. Date of procedure
 4. Other clinical information
 a. Relevant history
 (1) Clinical findings
 (2) Past ocular history
 (3) Previous ocular surgery
 (4) Previous treatment
 b. Relevant findings (eg, liver function tests,
 ultrasound)
 c. Clinical diagnosis
 d. Procedure (usually enucleation)
 e. Operative findings
 f. Anatomic site of specimen (right or left
 eye)
 5. Documentation of areas marked by surgeon
 for orientation (eg, suture, diagram)
 B. Macroscopic examination
 1. Specimen
 a. Organ(s)/tissue(s) included
 b. Unfixed/fixed (specify fixative) (note C)
 c. Orientation (note D)
 d. Description of other tissues, as appropriate
 e. Results of intraoperative consultation
 2. Globe
 a. Evidence of previous excision or treatment
 b. Note if previously opened/sectioned and
 in what fashion (note E)
 c. Size
 (1) Anteroposterior, horizontal, vertical dimensions
 of globe
 (2) Length and diameter of attached optic
 nerve
 (3) Corneal horizontal and vertical diameter
 (4) Diameter of pupil, if visible
 d. Transillumination (helpful to identify location
 of tumor and measure basal dimension
 prior to sectioning globe)
 (1) Quality of transillumination (eg, poor
 light transillumination, transilluminates
 light well)
 (2) Transillumination defect
 i. Location
 ii. Relationship to equator of globe
 iii. Relationship to limbus
 iv. Clock hour(s) of iris/globe
 v. Size (2 dimensions)
 e. Mark outline with marking implement
 f. Extrascleral extension, if present
 g. Sectioning of specimen (globe) (note E)
 h. Mass/tumor, if present
 (1) Location
 (2) Size (notes F and G)
 i. Base at cut edge (ie, portion of tumor
 closest to sclera)
 ii. Height at cut edge
 (3) Distance of anterior margin of tumor
 base from limbus at cut edge
 (4) Distance of posterior margin of tumor
 base from edge of optic disc
 (5) Other descriptive features (color, consistency,
 shape)
 (6) Structures involved and extent (note G)
 i. Retinal involvement
 ii. Optic nerve involvement
 iii. Macroscopic involvement of vitreous
 iv. Involvement of ciliary body
 v. Macroscopic involvement of anterior
 chamber angle
 i. Features of other (uninvolved) ocular tissues
 (1) Cornea (eg, clear, cloudy, opaque)
 (2) Anterior chamber (eg, deep, shallow,
 flat)
 (3) Angle (eg, open, narrow, closed)
 (4) Iris (eg, color, any abnormalities)
 (5) Ciliary body
 (6) Lens (eg, clear, cataractous, presence of
 lens implant, absence)
 (7) Vitreous (eg, color, consistency, hemorrhage)
 (8) Retina (eg, detachment, total or partial;
 hemorrhages)
 (9) Choroid
 (10) Sclera (eg, thinning, defects)
 (11) Optic disc (eg, pallor, increased cup/
 disc ratio)
 3. Tissues submitted for microscopic examination
 (specify) (note E)
 4. Special studies (specify) (eg, immunohistochemistry)
 C. Microscopic evaluation
 1. Tumor
 a. Site (choroid, ciliary body, iris) (note G)
 b. Histologic type (note A)
 c. Histologic grade
 d. Extent of invasion (note G)
 e. Size (note F)
 f. Anatomic extent (notes B and G)
 (1) Anterior margin of tumor
 (2) Retinal or scleral involvement
 (3) Angle involvement
 (4) Vitreal involvement
 (5) Optic nerve involvement
 2. Margins
 a. Extrascleral extension (notes B and G)
 b. Surgical margin of optic nerve (note B)
 3. Other prognostic features (note B)
 4. Additional pathologic findings, if present
 a. Cancer-related
 (1) Cataract
 (2) Vitreous hemorrhage
 (3) Glaucomatous optic atrophy
 (4) Secondary angle closure
 (5) Secondary open-angle glaucoma
 (6) Iris neovascularization
 (7) Retinal atrophy
 b. Other
 (1) Corneal disease
 (2) Diabetic retinopathy
 5. Results/status of special studies (specify)
 6. Comments
 a. Correlation with intraoperative consultation
 b. Correlation with other specimens, as appropriate
 c. Correlation with clinical information, as
 appropriate


EXPLANATORY NOTES

A: Histologic Type.--The modified Callender classification shown below is used for determining cell type, but has prognostic significance only for tumors of the choroid and ciliary body, not those of the iris, which generally have a benign course.[1-4]
Spindle cell nevus: slender cells with fusiform nuclei, delicate
 nuclear chromatin, and inapparent nucleoli; no
 mitoses are found
Spindle cell melanoma(*)
 Spindle A: slender cells with a thin oval nucleus, indistinct
 nucleoli, and often a longitudinal fold in the nuclear
 membrane
 Spindle B: larger plumper nuclei with sharply defined,
 round nucleoli
Mixed cell melanoma: both spindle and epithelioid cells
 present
Epithelioid cell melanoma(*): larger, more pleomorphic, polygonal
 cells with large, sometimes multiple nucleoli

 (*) Spindle cell melanomas have the most favorable prognosis
and epithelioid cell melanomas the least favorable in
terms of survival.


B: Other Pathologic Features of Prognostic Significance.--Other histologic features with prognostic significance in choroidal and ciliary body melanoma include the number of mitoses in 40 high-power fields, pigmentation, degree of inflammation, growth pattern (diffuse choroidal melanomas and ring melanomas of the ciliary body have a much less favorable prognosis), location of anterior margin of tumor, degree and patterns of vascularity, blood vessel invasion (both tumor vessels and normal vessels), tumor necrosis, extraocular extension, and optic nerve involvement.[4-15]

C: Fixative.--The minimum recommended fixation time for whole globes with intraocular tumors is 48 hours. The globe should be fixed in an adequate volume of fixative with at least a 10:1 ratio of fixative volume to specimen volume recommended. Incisions or windows in the globe are not necessary for adequate penetration of fixative and are not recommended. Injection of fixative into the globe is also not recommended (due to the possibility of introducing artifact).

D: Orientation.--The orientation of a globe may be determined by identification of extraocular muscle insertions, the optic nerve, and other landmarks, as illustrated in Figure 1. The terms temporal and nasal are generally used in place of lateral and medial with reference to ocular anatomy.

[ILLUSTRATION OMITTED]

E: Sectioning the Globe.--The globe is generally sectioned in the horizontal or vertical plane with care to include the pupil and optic nerve along with tumor/mass in the section to be submitted for microscopic examination. If the mass cannot be included with horizontal or vertical sectioning, the globe is sectioned obliquely to include the tumor, pupil, and optic nerve, as illustrated in Figure 2. Alternative methods of sectioning have been described.[16]

F: Tumor Size.--Tumor size has prognostic significance. Many studies of choroidal and ciliary body melanoma have defined small tumors as being less than 10 mm in greatest diameter.[4] More recently, an ongoing study started in 1986, the Collaborative Ocular Melanoma Study,[17,18] defined the following size classification based on clinical measurements.
Small tumors(*): smaller than medium or large tumors
 defined below

Medium tumors: [is greater than] 2.5 mm and
 [is less than] 10 mm in height, and
 [is less than] 16 mm in basal diameter

Large tumors: [is greater than] 10 mm in height or
 [is greater than] 2 mm in height and
 [is greater than] 16 mm in basal diameter or
 [is greater than] 8 mm in height with optic nerve
 involvement

(*) Small tumors have a more favorable prognosis.[6,7]


G: TNM Stage Groupings.--The American Joint Committee on Cancer (AJCC)/International Union Against Cancer (UICC) TNM staging systems for uveal melanoma of the iris, ciliary body, and choroid are shown below.[19]

IRIS

Tumor (T)
TX Primary tumor cannot be assessed
T0 No evidence of primary tumor
T1 Tumor limited to the iris
T2 Tumor involves 1 quadrant or less, with invasion
 into the anterior chamber angle
T3 Tumor involves more than 1 quadrant, with
 invasion into the anterior chamber angle, ciliary
 body, and/or choroid
T4 Tumor with extraocular invasion


Regional Lymph Nodes (N)
NX Regional lymph nodes cannot be assessed
N0 No regional lymph node metastasis
N1 Regional lymph node metastasis


Distant Metastasis (M)
MX Presence of distant metastasis cannot be assessed
M0 No distant metastasis
M1 Distant metastasis


CILIARY BODY

Tumor (T)
TX Primary tumor cannot be assessed
T0 No evidence of primary tumor
T1(*) Tumor limited to the ciliary body
T2 Tumor invades into the anterior chamber and/
 or iris
T3 Tumor invades choroid
T4 Tumor with extraocular invasion


Regional Lymph Nodes (N)
NX Regional lymph nodes cannot be assessed
N0 No regional lymph node metastasis
N1 Regional lymph node metastasis


Distant Metastasis (M)
MX Presence of distant metastasis cannot be assessed
M0 No distant metastasis
M1 Distant metastasis


CHOROID

Tumor (T)
TX Primary tumor cannot be assessed
T0 No evidence of primary tumor
TI(*) Tumor [is less than or equal to] 10 mm
 in greatest dimension with an
 elevation of [is less than or equal to] 3 mm
 T1a Tumor [is less than or equal to] 7 mm in
 greatest dimension with an elevation of
 [is less than or equal to] 2 mm
 T1b Tumor [is greater than] 7 mm but
 [is less than or equal to] 10 mm in
 greatest dimension with an elevation of
 [is greater than] 2 mm but
 [is less than or equal to] 3 mm
T2(*) Tumor [is greater than] 10 mm but
 [is less than or equal to] 15 mm
 in greatest dimension with an elevation
 [is greater than] 3 mm but
 [is less than or equal to] 5 mm
T3(*) Tumor [is greater than] 15 mm in greatest
 dimension or with an elevation
 [is greater than] 5 mm
T4 Tumor with extraocular invasion

(*) In clinical practice, the tumor base may be estimated
in optic disc diameters (dd) (average: 1 dd = 1.5 mm).
The elevation may be estimated in diopters (average 3 diopters
= 1 mm). Other techniques used, such as ultrasonography
and computerized stereometry, may provide a
more accurate measurement.

Note.--When dimension and elevation show a difference
in classification, the highest category should be used
for classification.


Regional Lymph Nodes (N)
NX Regional lymph nodes cannot be assessed
N0 No regional lymph node metastasis
N1 Regional lymph node metastasis


Distant Metastasis (M)
MX Presence of distant metastasis cannot be assessed
M0 No distant metastasis
M1 Distant metastasis


TNM Stage Groupings for Uveal Melanoma of the Iris or Ciliary Body
Stage I T1 N0 M0
Stage II T2 N0 M0
Stage III T3 N0 M0
Stage IVA T4 N0 M0
Stage IVB Any T N1 M0
 Any T Any N M1


TNM Stage Groupings for Uveal Melanoma of the Choroid
Stage IA T1a N0 M0
Stage IB T1b N0 M0
Stage II T2 N0 M0
Stage III T3 N0 M0
Stage IVA T4 N0 M0
Stage IVB Any T N1 M0
 Any T Any N M1


It should be noted that regional lymph node involvement is rare in uveal melanoma. Metastasis to the liver and direct extension into the orbit are more common.[19]

References

[1.] Callender GR. Malignant melanotic tumors of the eye: a study of histologic types in 111 cases. Trans Am Acad Ophthalmol Otolaryngol. 1931;36:131-142.

[2.] McLean IW, Zimmerman LE, Evans RM. Reappraisal of Callender's spindle A type of malignant melanoma of choroid and ciliary body. Am J Ophthalmol. 1978;86:557-564.

[3.] McLean IW, Foster WD, Zimmerman LE. Modifications of Callender's classification of uveal melanoma at the Armed Forces Institute of Pathology. Am J Ophthalmol. 1983;96:502-509.

[4.] Zimmerman LE. Malignant melanoma of the uveal tract. In: Spencer WH, ed. Ophthalmic Pathology: An Atlas and Textbook. 3rd ed. Philadelphia, Pa: WB Saunders Co; 1986:2072-2139.

[5.] Font RL, Spaulding AG, Zimmerman LE. Diffuse malignant melanoma of the uveal tract: a clinicopathologic report of 54 cases. Trans Am Acad Ophthalmol Otolaryngol. 1968;72:877-894.

[6.] McLean IW, Foster WD, Zimmerman LE. Prognostic factors in small malignant melanomas of choroid and ciliary body. Arch Ophthalmol. 1977;95:48-58.

[7.] Affeldt JC, Minckler DS, Azen SP, Yeh L. Prognosis in uveal melanoma with extraocular extension. Arch Ophthalmol. 1980;98:1975-1979.

[8.] McLean IW, Foster WD, Zimmerman LE. Uveal melanoma: location, size, cell type, and enucleation as risk factors in metastasis. Hum Pathol. 1982;13:123-132.

[9.] Weinhaus RS, Seddon JM, Albert DM, Gragoudas ES, Robinson N. Prognostic factor study of survival after enucleation for juxtapapillary melanomas. Arch Ophthalmol. 1985;103:1673-1677.

[10.] Gamel JW, McCurdy JB, McLean IW. A comparison of prognostic covariates for uveal melanoma. Invest Ophthalmol Vis Sci. 1992;33:1919-1922.

[11.] Folberg R, Pe'er J, Gruman LM, et al. The morphologic characteristics of tumor blood vessels as a marker of tumor progression in primary human uveal melanoma: a matched case-control study. Hum Pathol. 1992;23:1298-1305.

[12.] Coleman K, Baak JP, Van Diest P, Mullaney J, Farrell M, Fenton M. Prognostic factors following enucleation of 111 uveal melanomas. Br J Ophthalmol. 1993;77:688-692.

[13.] Folberg R, Rummelt V, Parys-Van Ginderdeuren R, et al. The prognostic value of tumor blood vessel morphology in primary uveal melanoma. Ophthalmology. 1993;100:1389-1398.

[14.] Folberg R, Rummelt V, Gruman LM, et al. Microcirculation architecture of melanocytic nevi and malignant melanomas of the ciliary body and choroid: a comparative histopathologic and ultrastructural study. Ophthalmology. 1994; 101: 718-727.

[15.] Rummelt V, Folberg R, Woolson RF, Hwang T, Pe'er J. Relation between the microcirculation architecture and the aggressive behavior of ciliary body melanomas. Ophthalmology. 1995;102:844-851.

[16.] Folberg R, Verdick R, Weingeist TA, Montague PR. The gross examination of eyes removed for choroidal and ciliary body melanomas. Ophthalmology. 1986;93:1643-1647.

[17.] The Collaborative Ocular Melanoma Study Group. Design and Methods of a Clinical Trial for a Rare Condition: the Collaborative Ocular Melanoma Study, COMS Report No. 3. Control Clin Trials. 1993;14:362-391.

[18.] Collaborative Ocular Melanoma Study: COMS Manual of Procedures. Springfield, Va: National Technical Information Service; 1989. NTIS accession PB90-115536.

[19.] Fleming ID, Cooper JS, Henson DE, et al, eds. AJCC Manual for Staging of Cancer. 5th ed. Philadelphia, Pa: Lippincott Raven; 1997.

Bibliography

Albert DM. Principles of pathology. In: Albert DM, Jakobiec FA, eds. Principles and Practice of Ophthalmology. Vol 4. Philadelphia, Pa: WB Saunders Co; 1994:2101-2126.

Albert DM, Dryja TP. The eye. In: Cotran RS, Kumar V, Robbins SL, eds. Pathologic Basis of Disease. 6th ed. Philadelphia, Pa: WB Saunders Co; 1998.

Yanoff MF, Fine BS. Ocular Pathology: A Text and Atlas. 3rd ed. Philadelphia, Pa: JB Lippincott Co; 1989:652-678.

Zimmerman LE. Malignant melanoma of the uveal tract. In: Spencer WH, ed. Ophthalmic Pathology: An Atlas and Textbook. 3rd ed. Philadelphia, Pa: WB Saunders Co; 1986:2072-2139.

Accepted for publication May 10, 2001.

From the Department of Ophthalmology, University of Wisconsin Hospital, Madison, Wis (Dr Albert); and the Departments of Ophthalmology and Pathology, Scheie Eye Institute, University of Pennsylvania, Philadelphia, Pa (Dr Syed).

This protocol was developed by the Cancer Committee of the College of American Pathologists and submitted for editorial review and publication. It represents the views of the Cancer Committee and is not the official policy of the College of American Pathologists.

Reprints: See Archives of Pathology & Laboratory Medicine Web site at www.cap.org.
COPYRIGHT 2001 College of American Pathologists
No portion of this article can be reproduced without the express written permission from the copyright holder.
Copyright 2001 Gale, Cengage Learning. All rights reserved.

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Author:Albert, Daniel; Syed, Nasreen
Publication:Archives of Pathology & Laboratory Medicine
Geographic Code:1USA
Date:Sep 1, 2001
Words:3125
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